from Jules: as the meeting ended the FDA’s Debra Birnkrant, M.D. Director, Division of Antiviral Products said this was a “landmark” meeting and indeed it was. The meeting started at 8am and ended at 8:30pm. However, this was not the longest meeting. This is the longest FDA Antiviral Ad Board meeting since the FDA hearing for ritonavir & indinavir, a joint hearing for both drugs on back to back days, the ritonavir hearing as I recall was held over night, the FDA & the sponsor had to meet in the hotel overnight & the meeting was resumed the next day, this was under FDA Commissioner Kessler, I was there. Both meeting were landmarks, the IDV/RTV & this one, this one because this is the first hearing to discuss approval for a prevention drug, which will open an unchartered era and will be full of surprises. The discussions today by the panel were controversial & complicated, as lots of concerns were raised including what baseline tests & monitoring tests should be used and how often, including testing for HIV, viral load, HBV, STIs, renal function, bone dexas and more.

By large majorities, the FDA’s Antiviral Drugs Advisory Committee voted to recommend extending Truvada’s license to include pre-exposure prophylaxis (PrEP) for men who have sex with men (MSM) and for HIV-discordant couples (with one partner positive and one negative). The advisory panel also supported Truvada (coformulated tenofovir/emtricitabine) as PrEP for “other individuals at risk for acquiring HIV through sexual activity,” but less enthusiastically than they endorsed the first two indications.

The committee voted 19 to 3 to recommend Truvada PrEP for HIV-negative MSM and 19 to 2 (with 1 abstention) for HIV-negative partners in serodiscordant couples. The vote favoring PrEP for “other individuals at risk for acquiring HIV through sexual activity” was 12 to 8 with 2 abstentions.

Committee members voiced uncertainty about who the “other individuals” are, although completed and ongoing trials offer ample suggestions. In the two placebo-controlled trials Gilead Sciences advanced to support the PrEP indication, participants were MSM in iPrEx [1] and HIV-discordant heterosexual African couples in Partners PrEP [2]. A third trial that found daily Truvada helps protect people from HIV during sex, TDF2, enrolled high-risk Batswana women and men not necessarily in discordant partnerships [3]. Some MSM in iPrEx lived in the US, but most were from South America, South Africa, and Thailand. These trials included no heterosexual US men or women.

A fourth trial, FEM-PrEP, found no protective effect with Truvada taken by high-risk African women [4], while the VOICE PrEP/microbicide trial closed its microbicide arm and its oral tenofovir-only arm because those strategies were not protecting high-risk women from HIV [5]. FEM-PrEP investigators found that only 15% of women who got HIV in the Truvada group had detectable tenofovir levels at two visits. In its briefing document for the Truvada PrEP hearing, the FDA noted that “adherence to prescribed interventions appears to play a key role” in success or failure of PrEP [6].

Both iPrEx and Partners PrEP randomized HIV-negative participants to Truvada or placebo; Partners PrEP also tested tenofovir alone to prevent HIV acquisition by HIV-negative partners with an HIV-positive partner. In their primary analyses, iPrEx documented a 42% lower HIV acquisition risk with Truvada, while Partners PrEP found a 75% lower risk with Truvada and a 67% lower risk with tenofovir alone. An FDA analysis presented at the hearing indicated that iPrEx men with measurable intracellular drug concentrations had an 87.5% lower risk of HIV infection than men taking placebo.

The licensing change formally requested by Gilead is that “Truvada is indicated for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection in adults.” Recommendation for an extended indication by the Antiviral Drugs Advisory Committee does not oblige the FDA to follow suit, but it seems likely the FDA will do so. On the way to the committee vote, FDA analysts presented a largely favorable review of Truvada PrEP findings, concluding that “safety and efficacy of [Truvada] for the prevention of HIV-1 infection in high-risk individuals is supported by two large clinical trials” [iPrEx and Partners PrEP].

Data presented by the iPrEx and Partners PrEP principal investigators showed that resistance did not emerge in anyone randomized to Truvada who became infected during the course of the trial. Resistance developed in a few people who took Truvada or tenofovir during early HIV infection that had gone undetected. Neither trial found evidence of risk compensation–the possibility that people using PrEP will ignore other measures that protect them from HIV, such as consistent condom use. In fact, study participants generally practiced safer sex after enrolling in the trials.

The FDA advised that “regular HIV testing, adherence and behavioral counseling on safer sex practices, including condom use, are essential components of healthcare delivery around PrEP.”

FDA officials did raise some safety concerns in their analysis of iPrEx and Partners PrEP. Noting that renal failure or Fanconi syndrome did not occur among Truvada takers in iPrEx, the FDA cautioned that cases of concurrent proteinuria, glycosuria, and hypophosphatemia primarily in the Truvada arm “may be potentially concerning for subclinical proximal renal tubulopathy, although the limited numbers and poor adherence observed in this trial, as assessed by drug level monitoring, preclude reliable interpretation” [6].

In Partners PrEP only 7 people permanently withdrew because of adverse events, and 6 withdrawals were attributed to grade 2 renal toxicity, 3 in people taking tenofovir alone, 2 in people taking Truvada, and 1 in the placebo group [6]. All renal toxicity (creatinine clearance below 50 mL/min) resolved in 5 women when they stopped study drugs. Results are pending on the 1 man who endured renal toxicity.

Truvada PrEP trials completed so far include few African-American men, who have a higher risk of renal disease than white men. And because HIV incidence has been climbing in African-American MSM, they are likely candidates for Truvada PrEP.

The FDA noted that men enrolled in iPrEx had lower bone mineral density (BMD) when they entered the trial than does the general population. Men randomized to Truvada had small but statistically significant drops in BMD compared with the placebo group throughout the trial. BMD declines of more than 5% from baseline affected 14% of iPrEx participants taking Truvada versus 6% taking placebo. The FDA pointed to similar BMD declines among MSM in a CDC study of tenofovir safety [7].

The FDA mentioned renal toxicity in its overall premeeting briefing conclusion of Truvada PrEP efficacy and safety: “The decision to prescribe [Truvada] for the prevention of sexual acquisition of HIV infection should carefully weigh the individual risks for acquiring HIV, their understanding of the importance of adherence to medication, and their potential for development of renal toxicity” [6].

Before clinicians start Truvada PrEP, the FDA said in its premeeting document, they should (1) test the person for HIV, (2) measure renal function and serum phosphorous, and (3) assess risk factors for renal and bone toxicity [6]. Clinicians might also consider supplementing vitamin D and calcium in someone taking Truvada PrEP, the FDA advised. Everyone using Truvada for PrEP should get tested regularly for HIV and monitored for renal problems. Some Truvada takers may benefit from DEXA bone scans before and during PrEP, the FDA suggested.

The FDA offered this final conclusion in its briefing document: “If physicians prescribe and individuals utilize [Truvada] in the manner described for PrEP, in combination with other strategies to prevent HIV infection, the individual at risk may be spared infection with a serious and life-threatening illness that requires lifelong treatment with a three-drug antiretroviral regimen. That regimen, in line with current treatment guidelines for HIV-infected treatment-naive patients, will almost certainly contain [Truvada]” [6].